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A Manganese Phosphate Nanocluster Activates the cGAS‐STING Pathway for Enhanced Cancer Immunotherapy
Author(s) -
Gao Min,
Xie YuQing,
Lei Kewen,
Zhao Yu,
Kurum Armand,
Van Herck Simon,
Guo Yugang,
Hu Xiaomeng,
Tang Li
Publication year - 2021
Publication title -
advanced therapeutics
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 0.125
0ISSN - 2366-3987
DOI - 10.1002/adtp.202100065
Subject(s) - nanoclusters , stimulator of interferon genes , cancer immunotherapy , sting , chemistry , immunotherapy , interferon , cancer research , cytotoxicity , microbiology and biotechnology , innate immune system , biochemistry , immune system , biology , immunology , receptor , in vitro , organic chemistry , engineering , aerospace engineering
Targeting the stimulator of interferon genes (STING) pathway with cyclic dinucleotides (CDNs), the natural STING agonists, is a promising immunotherapeutic strategy for cancer. However, the clinical application of natural CDNs as therapeutics is greatly hindered by their intrinsic properties including negative charges, small molecular weight, and high susceptibility to enzymatic degradation. Mn 2+ ions have been recently discovered to directly activate the cyclic GMP‐AMP (cGAMP) synthase (cGAS) and augment cGAMP‐STING binding affinity. Here, a PEGylated manganese(II) phosphate (MnP‐PEG) nanocluster is developed with high biocompatibility and potent capacity to stimulate the cGAS‐STING pathway. MnP‐PEG nanoclusters activate the immature bone marrow‐derived dendritic cells (DCs) leading to 57.3‐ and 13.3‐fold higher production of interferon β and interleukin‐6 than free cGAMP, respectively. The potent STING activation capacity is likely due to the efficient cellular internalization of MnP‐PEG nanoclusters by DCs and acid‐triggered release of Mn 2+ ions in the endolysosomes. Intratumoral administration of MnP‐PEG nanoclusters markedly enhances tumor infiltration as well as maturation of DCs and macrophages, and promotes activation and cytotoxicity of T cells and natural killer cells in the tumor. MnP‐PEG nanocluster in combination with a checkpoint inhibitor leads to significant tumor regression in the B16F10 murine melanoma model without any overt toxicities.